Changes in protein conformation and assembly underlie most processes in cell biology; correspondingly, defects in conformation and assembly are responsible for many human illnesses, including neurodegenerative diseases. Among the most common of these diseases is Parkinson's disease (PD) with a prevalence of approximately 2% after age 65. One of the hallmarks of PD is the presence of cytoplasmic inclusions in neuronal cells, which mainly contain the protein alpha-synuclein (aSyn). The presence of these inclusions of misfolded aSyn is associated with cell death, but the mechanism for toxicity and indeed the function of aSyn remain elusive. We have developed a system to investigate the biological function of aSyn and the toxicity related to its misfolding in the yeast (Saccharomyces cerevisiae). The behavior of aSyn in yeast cells correlates remarkably well with its behavior in mammalian cells. Our goal is to take advantage of the many genetic and molecular techniques available in yeast to investigate the normal and toxic functions of aSyn. We will 1) investigate the cellular quality-control mechanisms influencing aSyn toxicity, 2) identify other modifiers of aSyn toxicity by high throughput screening and 3) determine how factors that modify aSyn toxicity affect a panel of cell biological and biochemical assays we have developed to enhance our understanding of normal and abnormal sSyn biology. Throughout these studies we will collaborate closely with our colleagues at the MGH/MIT Morris Udall Center of Excellence in PD Research to ensure that our results are rapidly assessed in mammalian systems, and reciprocally that the power of yeast genetic and cell biological assays can be employed to facilitate our understanding of any candidate proteins found in the mammalian systems. Our ultimate aim is the development of new strategies for the prevention and treatment of Parkinson's disease.